The STRAT-PARK cohort: A personalized initiative to stratify Parkinson's disease.

The STRAT-PARK initiative aims to provide a platform for stratifying Parkinson's disease (PD) into biological subtypes, using a bottom-up, multidisciplinary biomarker-based and data-driven approach. PD is a heterogeneous entity, exhibiting high interindividual clinicopathological variability. This diversity suggests that PD may encompass multiple distinct biological entities, each driven by different molecular mechanisms. Molecular stratification and identification of disease subtypes is therefore a key priority for understanding and treating PD. STRAT-PARK is a multi-center longitudinal cohort aiming to recruit a total of 2000 individuals with PD and neurologically healthy controls from Norway and Canada, for the purpose of identifying molecular disease subtypes. Clinical assessment is performed annually, whereas biosampling, imaging, and digital and neurophysiological phenotyping occur every second year. The unique feature of STRAT-PARK is the diversity of collected biological material, including muscle biopsies and platelets, tissues particularly useful for mitochondrial biomarker research. Recruitment rate is ∼150 participants per year. By March 2023, 252 participants were included, comprising 204 cases and 48 controls. STRAT-PARK is a powerful stratification initiative anticipated to become a global research resource, contributing to personalized care in PD.

Effects of speech rate modifications on phonatory acoustic outcomes in Parkinson's disease.

Speech rate reduction is a global speech therapy approach for speech deficits in Parkinson's disease (PD) that has the potential to result in changes across multiple speech subsystems. While the overall goal of rate reduction is usually improvements in speech intelligibility, not all people with PD benefit from this approach. Speech rate is often targeted as a means of improving articulatory precision, though less is known about rate-induced changes in other speech subsystems that could help or hinder communication. The purpose of this study was to quantify phonatory changes associated with speech rate modification across a broad range of speech rates from very slow to very fast in talkers with and without PD. Four speaker groups participated: younger and older healthy controls, and people with PD with and without deep brain stimulation of the subthalamic nucleus (STN-DBS). Talkers read aloud standardized sentences at 7 speech rates elicited using magnitude production: habitual, three slower rates, and three faster rates. Acoustic measures of speech intensity, cepstral peak prominence, and fundamental frequency were measured as a function of speech rate and group. Overall, slower rates of speech were associated with differential effects on phonation across the four groups. While all talkers spoke at a lower pitch in slow speech, younger talkers showed increases in speech intensity and cepstral peak prominence, while talkers with PD and STN-DBS showed the reverse pattern. Talkers with PD without STN-DBS and older healthy controls behaved in between these two extremes. At faster rates, all groups uniformly demonstrated increases in cepstral peak prominence. While speech rate reductions are intended to promote positive changes in articulation to compensate for speech deficits in dysarthria, the present results highlight that undesirable changes may be invoked across other subsystems, such as at the laryngeal level. In particular, talkers with STN-DBS, who often demonstrate speech deterioration following DBS surgery, demonstrated more phonatory detriments at slowed speech rates. Findings have implications for speech rate candidacy considerations and speech motor control processes in PD.

Neuropsychiatric symptoms and brain morphology in patients with mild cognitive impairment, cerebrovascular disease and Parkinson disease: A cross sectional and longitudinal study.

OBJECTIVES: Neuropsychiatric symptoms (NPS) increase risk of developing dementia and are linked to various neurodegenerative conditions, including mild cognitive impairment (MCI due to Alzheimer's disease [AD]), cerebrovascular disease (CVD), and Parkinson's disease (PD). We explored the structural neural correlates of NPS cross-sectionally and longitudinally across various neurodegenerative diagnoses. METHODS: The study included individuals with MCI due to AD, (n = 74), CVD (n = 143), and PD (n = 137) at baseline, and at 2-years follow-up (MCI due to AD, n = 37, CVD n = 103, and PD n = 84). We assessed the severity of NPS using the Neuropsychiatric Inventory Questionnaire. For brain structure we included cortical thickness and subcortical volume of predefined regions of interest associated with corticolimbic and frontal-executive circuits. RESULTS: Cross-sectional analysis revealed significant negative correlations between appetite with both circuits in the MCI and CVD groups, while apathy was associated with these circuits in both the MCI and PD groups. Longitudinally, changes in apathy scores in the MCI group were negatively linked to the changes of the frontal-executive circuit. In the CVD group, changes in agitation and nighttime behavior were negatively associated with the corticolimbic and frontal-executive circuits, respectively. In the PD group, changes in disinhibition and apathy were positively associated with the corticolimbic and frontal-executive circuits, respectively. CONCLUSIONS: The observed correlations suggest that underlying pathological changes in the brain may contribute to alterations in neural activity associated with MBI. Notably, the difference between cross-sectional and longitudinal results indicates the necessity of conducting longitudinal studies for reproducible findings and drawing robust inferences.

Botulinum Toxin Injections to the Obliquus Capitis Inferioris Muscle for Dynamic Cervical Dystonia Improves Subjective Patient Outcomes.

The obliquus capitis inferioris (OCI) muscle is a significant driver of cervical dystonia with torticaput movements and a no-no head tremor. Limited data are available on the efficacy of OCI injections on patient outcomes. Our study aims to determine whether the botulinum toxin injection into OCI improves subjective patient quality of life in those with dystonic head tremors. A retrospective chart review was performed for 25 patients receiving injections into the OCI for a dystonic head tremor at the London Movement Disorders Clinic between January 2020 and January 2022. Toronto Western Spasmodic Torticollis Scale-2 (TWSTRS-2) subscale scores for disability and pain, TWSTRS-PSYCH scores, and the global impression of severity were extracted. The average TWSTRS-2 disability subscale change was -2.8 points (p < 0.003). The average TWSTRS-2 pain subscale change was -4.6 points (p < 0.003). The average TWSTRS-PSYCH score prior to injection was 5.6. After injection, the average score was 3.7 (p < 0.004). The patient self-reported average global impression of severity before injection was 7.0; after this, it was 4.2 (p < 0.0003). The OCI injection showed significant improvement in retrospective patient self-reported outcomes; it should be considered early in the treatment plan for cervical dystonia with a no-no head tremor.

Force Control Issues in Upper and Lower Limbs in Parkinson's Disease and Freezing of Gait.

Parkinson's Disease (PD) has been found to cause force control deficits in upper and lower limbs. About 50% of patients with advanced PD develop a debilitating symptom called freezing of gait (FOG), which has been linked to force control problems in the lower limbs, and some may only have a limited response to the gold standard pharmaceutical therapy, levodopa, resulting in partially levodopa-responsive FOG (PLR-FOG). There has been limited research on investigating upper-limb force control in people with PD with PLR-FOG, and without FOG. In this pilot study, force control was explored using an upper-and-lower-limb haptics-enabled robot in a reaching task while people with PD with and without PLR-FOG were on their levodopa medication. A healthy control group was used for reference, and each cohort completed the task at three different levels of assistance provided by the robot. Similar significant proportional force control deficits were found in the upper and lower limbs in patients with PLR-FOG versus those without FOG. Some aspects of force control were found to be retained, including an ability to increase or decrease force in response to changes in resistance while completing a reaching task. Overall, these results suggest there are force control deficits in both the upper and lower limbs in people with PLR-FOG.

Robotics-Based Characterization of Sensorimotor Integration in Parkinson's Disease and the Effect of Medication.

Integration of multi-modal sensory inputs and modulation of motor outputs based on perceptual estimates is called Sensorimotor Integration (SMI). Optimal functioning of SMI is essential for perceiving the environment, modulating the motor outputs, and learning or modifying motor skills to suit the demands of the environment. Growing evidence suggests that patients diagnosed with Parkinson's Disease (PD) may suffer from an impairment in SMI that contributes to perceptual deficits, leading to motor abnormalities. However, the exact nature of the SMI impairment is still unclear. This study uses a robot-assisted assessment tool to quantitatively characterize SMI impairments in PD patients and how they affect voluntary movements. A set of assessment tasks was developed using a robotic manipulandum equipped with a virtual-reality system. The sensory conditions of the virtual environment were varied to facilitate the assessment of SMI. A hundred PD patients (before and after medication) and forty-three control subjects completed the tasks under varying sensory conditions. The kinematic measures obtained from the robotic device were used to evaluate SMI. The findings reveal that across all sensory conditions, PD patients had 36% higher endpoint error, 38% higher direction error in reaching tasks, and 43% higher number of violations in tracing tasks than control subjects due to impairment in integrating sensory inputs. However, they still retained motor learning ability and the ability to modulate motor outputs. The medication worsened the SMI deficits as PD patients, after medication, performed worse than before medication when encountering dynamic sensory environments and exhibited impaired motor learning ability.

White matter hyperintensities and smaller cortical thickness are associated with neuropsychiatric symptoms in neurodegenerative and cerebrovascular diseases.

BACKGROUND: Neuropsychiatric symptoms (NPS) are a core feature of most neurodegenerative and cerebrovascular diseases. White matter hyperintensities and brain atrophy have been implicated in NPS. We aimed to investigate the relative contribution of white matter hyperintensities and cortical thickness to NPS in participants across neurodegenerative and cerebrovascular diseases. METHODS: Five hundred thirteen participants with one of these conditions, i.e. Alzheimer's Disease/Mild Cognitive Impairment, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Parkinson's Disease, or Cerebrovascular Disease, were included in the study. NPS were assessed using the Neuropsychiatric Inventory - Questionnaire and grouped into hyperactivity, psychotic, affective, and apathy subsyndromes. White matter hyperintensities were quantified using a semi-automatic segmentation technique and FreeSurfer cortical thickness was used to measure regional grey matter loss. RESULTS: Although NPS were frequent across the five disease groups, participants with frontotemporal dementia had the highest frequency of hyperactivity, apathy, and affective subsyndromes compared to other groups, whilst psychotic subsyndrome was high in both frontotemporal dementia and Parkinson's disease. Results from univariate and multivariate results showed that various predictors were associated with neuropsychiatric subsyndromes, especially cortical thickness in the inferior frontal, cingulate, and insula regions, sex(female), global cognition, and basal ganglia-thalamus white matter hyperintensities. CONCLUSIONS: In participants with neurodegenerative and cerebrovascular diseases, our results suggest that smaller cortical thickness and white matter hyperintensity burden in several cortical-subcortical structures may contribute to the development of NPS. Further studies investigating the mechanisms that determine the progression of NPS in various neurodegenerative and cerebrovascular diseases are needed.

Visual velocity perception dysfunction in Parkinson's disease.

OBJECTIVE: Compared with motor deficits, sensory information processing in Parkinson's disease (PD) is relatively unexplored. While there is increasing interest in understanding the sensory manifestations of PD, the extent of sensory abnormality in PD has remained relatively unexplored. Furthermore, most investigations on the sensory aspects of PD involve motor aspects, causing confounding results. As sensory deficits often arise in early PD development stages, they present a potential technological target for diagnosis and disease monitoring that is affordable and accessible. Considering this, the current study's aim is to assess visual spatiotemporal perception independent of goal directed movements in PD by designing and using a scalable computational tool. METHODS: A flexible 2-D virtual reality environment was created to evaluate various cases of visual perception. Using the tool, an experimental task quantifying the visual perception of velocity was tested on 37 individuals with PD and 17 age-matched control participants. RESULTS: PD patients, both ON and OFF PD therapy, displayed perceptual impairments (p = 0.001 and p = 0.008, respectively) at slower tested velocity magnitudes. These impairments were even observed in early stages of PD (p = 0.015). CONCLUSION: Visual velocity perception is impaired in PD patients, which suggests impairments in visual spatiotemporal processing occur in PD and provides a promising modality to be used with disease monitoring software. SIGNIFICANCE: Visual velocity perception shows high sensitivity to PD at all stages of the disease. Dysfunction in visual velocity perception may contribute to observed motor dysfunction in PD.

Conversion to AbobotulinumtoxinA Increases Waning Time and Efficacy for Cervical Dystonia.

Background: Symptom re-emergence before re-injection negatively impacts cervical dystonia (CD) patients receiving botulinum toxin type A (BoNT-A) therapy. Longer waning time is associated with abobotulinumtoxinA (abo-BoNT-A) as compared to onabotulinumtoxinA (ona-BoNT-A)/incobotulinumtoxinA (inco-BoNT-A) formulations. Objectives: To compare waning time and treatment outcomes when chronically injected CD patients experiencing early waning despite being optimized on BoNT-A (ona-BoNT-A/inco-BoNT-A) were converted to abo-BoNT-A. Methods: Thirty-three chronically injected CD participants with a waning time of ≤8 weeks were converted to abo-BoNT-A (1:2.5 dose ratio) for three injections every 12-weeks. The second and third injection patterns were kinematically optimized. Participants were converted back to their original BoNT-A for the fourth injection (1:2.5) using the same third abo-BoNT-A pattern. Participant-perceived waning times were collected post-injections. Clinical scales (Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)) and kinematic measures were collected 12-weeks post-injection and at three peak effect time-points. Results: Compared to baseline, waning time (12-22 days) significantly increased following all abo-BoNT-A treatments (P < 0.005) but was not significantly different at the fourth injection (original BoNT-A reconversion). TWSTRS sub-scores significantly reduced following all abo-BoNT-A treatments (P < 0.0001) and at peak effect following the third injection compared to original BoNT-A. Dysphagia and muscle weakness were reported and comparable to safety of original BoNT-A formulations. Conclusions: Optimized patients experiencing waning had significant improvement in the peak benefit as well as the duration of effect when converted to abo-BoNT-A. This effect was toxin dependent as reconversion to the original BoNT-A using the kinematically optimized pattern failed to produce an improvement in waning.

A Comparison of Voice Amplifiers and Personal Communication Systems for Hypophonia: An Exploration of Communicative Participation.

PURPOSE: The primary purpose of this study was to evaluate how individuals with hypophonia (HP; also referred to as HP participants) and their primary communication partners (PCPs; also referred to as PCP participants) rate communicative participation before and after experience with a speech amplification device. A secondary purpose was to evaluate pre- and post-device effects on self-rated communicative participation for each of the three speech amplification devices trialed outside of the laboratory. METHOD: Seventeen individuals with HP and their PCPs participated in a crossover design study that compared three different amplification devices: a wired belt-pack amplifier, a wireless stationary amplifier, and a personal frequency modulation (FM) system. Both the individuals with HP and their PCPs self-rated communicative participation at baseline and after trialing each device following 1-week device trial periods at home. Patient-reported outcome measures included the Communicative Effectiveness Survey (CES) and the Voice Activity and Participation Profile (VAPP). Following study completion, participants indicated whether they would like to select a specific device to continue using. RESULTS: Overall, HP participants rated communicative participation following device use higher than that in the pre-device condition, with the FM system resulting in the overall highest VAPP ratings and second highest CES ratings. Furthermore, HP and PCP participants rated these measures similarly. Finally, HP participants who selected a device to continue using self-reported lower total communicative effectiveness scores and greater voice activity limitations and participation restrictions at baseline in comparison to the nonselectors. CONCLUSIONS: This study contributes to an increased understanding of how communicative participation is experienced within this clinical population resulting from speech amplification. It is suggested that the inclusion of participation-based outcome measurement is essential to ensure a multidimensional and comprehensive approach to device prescription for individuals with HP.

Robot-assisted investigation of sensorimotor control in Parkinson's disease.

Sensorimotor control (SMC) is a complex function that involves sensory, cognitive, and motor systems working together to plan, update and execute voluntary movements. Any abnormality in these systems could lead to deficits in SMC, which would negatively impact an individual's ability to execute goal-directed motions. Recent studies have shown that patients diagnosed with Parkinson's disease (PD) have dysfunctions in sensory, motor, and cognitive systems, which could give rise to SMC deficits. However, SMC deficits in PD and how they affect a patient's upper-limb movements have not been well understood. The objective of the study was to investigate SMC deficits in PD and how they affect the planning and correction of upper-limb motions. This was accomplished using a robotic manipulandum equipped with a virtual-reality system. Twenty age-matched healthy controls and fifty-six PD patients (before and after medication) completed an obstacle avoidance task under dynamic conditions (target and obstacles in moving or stationary form, with and without mechanical perturbations). Kinematic information from the robot was used to extract eighteen features that evaluated the SMC functions of the participants. The findings show that the PD patients before medication were 32% slower, reached 16% fewer targets, hit 41% more obstacles, and were 26% less efficient than the control participants, and the difference in these features was statistically significant under dynamic conditions. In addition to the motor deficits, the PD patients also showed deficits in handling high cognitive loads and interpreting sensory cues. Further, the PD patients after medication exhibited worse sensory and cognitive performance than before medication under complex testing conditions. The PD patients also showed deficits in following the computational models leading to poor motor planning.

Classification and staging of Parkinson's disease using video-based eye tracking.

INTRODUCTION: 83% of those diagnosed with Parkinson's Disease (PD) eventually progress to PD with mild cognitive impairment (PD-MCI) followed by dementia (PDD) - suggesting a complex spectrum of pathology concomitant with aging. Biomarkers sensitive and specific to this spectrum are required if useful diagnostics are to be developed that may supplement current clinical testing procedures. We used video-based eye tracking and machine learning to develop a simple, non-invasive test sensitive to PD and the stages of cognitive dysfunction. METHODS: From 121 PD (45 Cognitively Normal/45 MCI/20 Dementia/11 Other) and 106 healthy controls, we collected video-based eye tracking data on an interleaved pro/anti-saccade task. Features of saccade, pupil, and blink behavior were used to train a classifier to predict confidence scores for PD/PD-MCI/PDD diagnosis. RESULTS: The Receiver Operator Characteristic Area Under the Curve (ROC-AUC) of the classifier was 0.88, with the cognitive-dysfunction subgroups showing progressively increased AUC, and the AUC of PDD being 0.95. The classifier reached a sensitivity of 83% and a specificity of 78%. The confidence scores predicted PD motor and cognitive performance scores. CONCLUSION: Biomarkers of saccade, pupil, and blink were extracted from video-based eye tracking to create a classifier with high sensitivity to the landscape of PD cognitive and motor dysfunction. A complex landscape of PD is revealed through a quick, non-invasive eye tracking task and our model provides a framework for such a task to be used as a supplementary screening tool in the clinic.

White matter hyperintensity burden predicts cognitive but not motor decline in Parkinson's disease: results from the Ontario Neurodegenerative Diseases Research Initiative.

BACKGROUND AND PURPOSE: The pathophysiology of Parkinson's disease (PD) negatively affects brain network connectivity, and in the presence of brain white matter hyperintensities (WMHs) cognitive and motor impairments seem to be aggravated. However, the role of WMHs in predicting accelerating symptom worsening remains controversial. The objective was to investigate whether location and segmental brain WMH burden at baseline predict cognitive and motor declines in PD after 2 years. METHODS: Ninety-eight older adults followed longitudinally from Ontario Neurodegenerative Diseases Research Initiative with PD of 3-8 years in duration were included. Percentages of WMH volumes at baseline were calculated by location (deep and periventricular) and by brain region (frontal, temporal, parietal, occipital lobes and basal ganglia + thalamus). Cognitive and motor changes were assessed from baseline to 2-year follow-up. Specifically, global cognition, attention, executive function, memory, visuospatial abilities and language were assessed as were motor symptoms evaluated using the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III, spatial-temporal gait variables, Freezing of Gait Questionnaire and Activities Specific Balance Confidence Scale. RESULTS: Regression analysis adjusted for potential confounders showed that total and periventricular WMHs at baseline predicted decline in global cognition (p < 0.05). Also, total WMH burden predicted the decline of executive function (p < 0.05). Occipital WMH volumes also predicted decline in global cognition, visuomotor attention and visuospatial memory declines (p < 0.05). WMH volumes at baseline did not predict motor decline. CONCLUSION: White matter hyperintensity burden at baseline predicted cognitive but not motor decline in early to mid-stage PD. The motor decline observed after 2 years in these older adults with PD is probably related to the primary neurodegenerative process than comorbid white matter pathology.

Neuropsychiatric Symptom Burden across Neurodegenerative Disorders and its Association with Function.

OBJECTIVE: Neuropsychiatric symptoms (NPS) are prevalent in neurodegenerative disorders, however, their frequency and impact on function across different disorders is not well understood. We compared the frequency and severity of NPS across Alzheimer's disease (AD) (either with mild cognitive impairment or dementia), Cerebrovascular disease (CVD), Parkinson's disease (PD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), and explored the association between NPS burden and function. METHODS: We obtained data from Ontario Neurodegenerative Disease Research Initiative (ONDRI) that included following cohorts: AD (N = 111), CVD (N = 148), PD (N = 136), FTD (N = 50) and ALS (N = 36). We compared the frequency and severity of individual NPS (assessed by the neuropsychiatric inventory questionnaire) across cohorts using generalized estimating equations and analysis of variance. Second, we assessed the relationship of NPS burden with instrumental (iADLs) and basic (ADLs) activities of living across cohorts using multivariate linear regression while adjusting for relevant demographic and clinical covariates. RESULTS: Frequency of NPS varied across cohorts (χ2(4) = 34.4, p < .001), with post-hoc tests showing that FTD had the greatest frequency as compared to all other cohorts. The FTD cohort also had the greatest severity of NPS (H(4) = 34.5, p < .001). Further, there were differences among cohorts in terms of the association between NPS burden and ADLs (F(4,461) = 3.1, p = 0.02). Post-hoc comparisons suggested that this finding was driven by the FTD group, however, the differences did not remain significant following Bonferroni correction. There were no differences among cohorts in terms of the association between NPS burden and IADLs. CONCLUSIONS: NPS frequency and severity are markedly greater in FTD as compared to other neurodegenerative diseases. Further, NPS burden appears to be associated differently with function across neurodegenerative disorders, highlighting the need for individualized clinical interventions.

Slowly Progressive Cerebellar Ataxia in a 55-Year-Old Female Patient.

A 55-year-old female patient with a history of hypercholesterolemia and anxiety presented for imbalance, fear of falling, and progressive disability. Examination revealed gaze-evoked horizontal nystagmus, ataxic dysarthria, sensory neuronopathy, and cerebellar atrophy. What is your diagnosis?

Characteristics of the Ontario Neurodegenerative Disease Research Initiative cohort.

INTRODUCTION: Understanding synergies between neurodegenerative and cerebrovascular pathologies that modify dementia presentation represents an important knowledge gap. METHODS: This multi-site, longitudinal, observational cohort study recruited participants across prevalent neurodegenerative diseases and cerebrovascular disease and assessed participants comprehensively across modalities. We describe univariate and multivariate baseline features of the cohort and summarize recruitment, data collection, and curation processes. RESULTS: We enrolled 520 participants across five neurodegenerative and cerebrovascular diseases. Median age was 69 years, median Montreal Cognitive Assessment score was 25, median independence in activities of daily living was 100% for basic and 93% for instrumental activities. Spousal study partners predominated; participants were often male, White, and more educated. Milder disease stages predominated, yet cohorts reflect clinical presentation. DISCUSSION: Data will be shared with the global scientific community. Within-disease and disease-agnostic approaches are expected to identify markers of severity, progression, and therapy targets. Sampling characteristics also provide guidance for future study design.

Real-World Longitudinal Experience of Botulinum Toxin Therapy for Parkinson and Essential Tremor.

BACKGROUND: Botulinum toxin type A (BoNT-A) therapy for upper-limb tremor has emerged as a promising option. However, it is unclear in real-world practices whether a technology-guided approach can compare with expert clinical assessments (including surface anatomy and palpation) for improving outcomes. This retrospective study aims to review our clinical outcomes of treating essential tremor (ET) and Parkinson's disease (PD) tremor using either clinical- or kinematic-based injection pattern determination methods. METHODS: 68 ET and 45 PD patients received at least one injection for their upper-limb tremor (unilateral or bilateral) in the last 7 years. Demographics of patients and BoNT-A injections were collected. A Mann-Whitney U statistical test was used to compare outcome measures between ET and PD cohorts. RESULTS: Mean age (72 ± 9 years), number of injections (5), years receiving therapy (~2 years), clinic- (~57%) or kinematic-based patterns, and self-paying (52%) were similar between both cohorts. BoNT-A as a monotherapy in both upper limbs was received in more ET than PD patients. Double reconstitution of Xeomin® in the wrist flexors/extensors, supinator, biceps, and triceps were most injected. Discontinuation due to no benefit/weakness was not dependent on the injection pattern determination approach. CONCLUSIONS: Kinematic-based BoNT-A injections produced similar treatment outcomes to injections based on the clinical expertise of the expert injector. This suggests that kinematics could be used by a non-expert to attain equivalent efficacy potentially improving access to this treatment.

Targeted copy number variant identification across the neurodegenerative disease spectrum.

BACKGROUND: Although genetic factors are known to contribute to neurodegenerative disease susceptibility, there remains a large amount of heritability unaccounted for across the diagnoses. Copy number variants (CNVs) contribute to these phenotypes, but their presence and influence on disease state remains relatively understudied. METHODS: Here, we applied a depth of coverage approach to detect CNVs in 80 genes previously associated with neurodegenerative disease within participants of the Ontario Neurodegenerative Disease Research Initiative (n = 519). RESULTS: In total, we identified and validated four CNVs in the cohort, including: (1) a heterozygous deletion of exon 5 in OPTN in an Alzheimer's disease participant; (2) a duplication of exons 1-5 in PARK7 in an amyotrophic lateral sclerosis participant; (3) a duplication of >3 Mb, which encompassed ABCC6, in a cerebrovascular disease (CVD) participant; and (4) a duplication of exons 7-11 in SAMHD1 in a mild cognitive impairment participant. We also identified 43 additional CNVs that may be candidates for future replication studies. CONCLUSION: The identification of the CNVs suggests a portion of the apparent missing heritability of the phenotypes may be due to these structural variants, and their assessment is imperative for a thorough understanding of the genetic spectrum of neurodegeneration.